The aim of this research program is to investigate mechanisms of protective immunity and immunopathology in schistosomiasis with the ultimate goal of immunologic intervention. Progress was achieved in the following areas during the year. A. Demonstration of IL-12-stimulated humoral immunity against schistosome infection. Interleukin-12, when coadministered repeatedly with an irradiated cercarial vaccine, was shown to boost protective humoral responses resulting in nearly complete resistance to challenge infection. B. Analysis of egg granuloma formation and downmodulation in knockout mice. Mice genetically deficient in IFN-gamma, IL-10 or CD8+ T cells were shown to undergo normal granuloma formation upon acute infection with S. mnsoni as well as downmodulate egg granuloma size during the chronic phase. In contrast, B cell (mu MT) knockout mice developed enlarged acute granulomas which failed to modulate in late infection. These studies thus reveal a major immunoregulatory function of B lymphocytes on schistosome egg pathology. C. Cross-regulatory cytokine function in spleen cells from hepatosplenic patients. Spleen cells from surgically splenectomized hepatosplenic patients showed in vitro cytokine responses comparable to peripheral blood mononuclear cells of the same individuals. Endogenous IL-10 was shown to be a potent downregulator of IFN-gamma and IL-12 Ag specific responses in these patients while exogenous IL-12 in some individuals restored suppressed IFN-gamma and IL-12 responses while stimulating IL-10 production.